Dual drug dosage forms with improved separation of drugs

ABSTRACT

Drug tablets that include a prolonged-release core and an immediate-release layer or shell are prepared with a thin barrier layer of drug-free polymer between the prolonged-release and immediate-release portions of the tablet. The barrier layer is penetrable by gastrointestinal fluid, thereby providing full access of the gastrointestinal fluid to the prolonged-release core, but remains intact during the application of the immediate-release layer, substantially reducing or eliminating any penetration of the immediate-release drug into the prolonged-release portion.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is in the field of pharmacology, and relates to drugdosage forms that are designed to deliver drugs concurrently in bothimmediate-release and prolonged-release delivery profiles.

2. Description of the Prior Art

Certain pharmacological therapies either require or benefit from thesequential administration of two or more drugs. While this can beaccomplished if the administration is done according to a strict timeschedule, many patients have difficulty complying with such a schedulewithout the assistance of a medical professional. Some therapies involveonly an immediate but rapidly declining high-level dosage and aprolonged dosage at a low or moderate level, the two dosages beingeither of the same drug or of a different drug. Even two-dosagetherapies such as these however can be troublesome to maintain if aseparate administration is needed for each dosage. Certainpharmaceutical formulations have therefore been developed that combineboth functions into a single dosage form. This simplifies the therapyand reduces or eliminates the chances of improper administration.

Many unitary dosage forms have been proposed that combine an immediaterelease drug with a prolonged release drug by placing the drugs indifferent layers of a tablet or by placing one drug in aquickly-dissolving or quickly-dispersing shell that surrounds the slowlydissolving or swellable core that contains the other drug. Theimmediate-release layer or shell is typically formed by coating thepre-formed prolonged-release portion with a solution or a suspension ofthe immediate-release drug and a polymer and then allowing the liquidcarrier in which the drug and polymer are dissolved or suspended toevaporate, leaving a solid dry outer layer. In some cases, however, theliquid carrier tends to cause swelling of the outer surface of theprolonged-release portion. As the prolonged-release matrix swells, someof the drug intended for immediate release enters the prolonged-releasematrix. When the immediate-release drug is applied as a suspension ofparticles, the particles tend to become trapped in the prolonged-releasematrix. High-potency drugs that are intended for immediate release aretherefore retained rather than released. The problem can be particularlyacute when the drug is insoluble or of low solubility, since unintendedretention of the drug in the prolonged-release portion can significantlyreduce the amount of the drug that is available for absorption into thepatient's bloodstream.

SUMMARY OF THE INVENTION

It has now been discovered that a drug dosage form that includes aprolonged-release core and an immediate-release layer or shell can bemanufactured in a manner that reduces or prevents any migration of drugfrom the immediate-release portion into the prolonged-release portion,by interposing a thin protective layer of drug-free polymer between theprolonged-release and immediate-release portions. The protective layeris penetrable by, or dissolved in, water or gastrointestinal fluid,thereby providing full access of the gastrointestinal fluid to theprolonged-release core. The protective layer remains intact howeverduring the application of the immediate-release layer, substantiallyreducing or eliminating any penetration by the immediate-release drug.The protective layer thereby allows immediate release of the entire doseof drug in the outer layer. The inclusion of the protective layer alsoserves to prevent interaction of the prolonged-release andimmediate-release drugs, which is of value in cases where interactionbetween the two drugs may be detrimental to the activity of either orboth of the drugs.

This discovery extends to dosage forms in which the immediate-releaselayer is applied either as a solution of the drug in an aqueous ororganic solvent or as a suspension of solid particles of the drug in anaqueous or organic liquid carrier. In most cases, the liquid carrieralso contains dissolved, dispersed or suspended polymer to assist in theformation of an immediate release coating. The discovery is ofparticular interest as applied to immediate-release layers applied assuspensions of solid particles, but also those that are applied assolutions. A disclosure of certain dosage forms in which theimmediate-release layer is prepared from particulate suspensions isfound in commonly owned, co-pending U.S. patent application Ser. No.10/066,146, filed Feb. 1, 2002, entitled “Manufacture of Oral DosageForms Delivering Both Immediate-Release and Sustained-Release Drugs,”Lim et al., inventors, the contents of which are incorporated herein byreference.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The dosage forms of this invention are designed for oral ingestion, andthe prolonged-release portion of the dosage form is one that deliversits drug to the digestive system continuously over a period of time ofat least an hour and preferably several hours. The drug is retained in amatrix or supporting body of pharmaceutically inert solid, and theprolonged delivery rate can be achieved by using a matrix that allowsthe gastrointestinal fluid to permeate the matrix and leach out the drug(i.e., allow the drug to diffuse out from the matrix as the drug slowlydissolves in the permeating fluid), or a matrix that slowly dissolves orerodes to expose the drug to the gastrointestinal fluid, or one thatdissolves or erodes while allowing the gastrointestinal fluid topermeate. The delivery rate is preferably slow enough that at leastabout 40% of the drug remains unreleased one hour after ingestion, morepreferably at least about 60% and most preferably at least about 80%. Inmost cases, the drug will be substantially all released within about tenhours and preferably within about eight hours, and in many cases, thematrix supporting the drug will remain substantially intact until all ofthe drug is released. “Substantially intact” in this sense means thatthe matrix retains at least most of its size and shape rather thandissolving or disintegrating into fragments. In this specification, theterm “prolonged-release” is equivalent to the terms “controlled-release”and “sustained-release” as used in the prior art.

In certain preferred embodiments of the invention, the supporting matrixin the prolonged-release portion of the tablet is a material that swellsupon contact with gastrointestinal fluid to a size that is large enoughto promote retention in the stomach while the subject is in thedigestive state, which is also referred to as the postprandial or “fed”mode. The “fed” mode is one of two modes of activity of the stomach thatdiffer by their distinctive patterns of gastroduodenal motor activity.The “fed” mode is induced by food ingestion and begins with a rapid andprofound change in the motor pattern of the upper gastrointestinal (GI)tract. The change consists of a reduction in the amplitude of thecontractions that the stomach undergoes and a reduction in the pyloricopening to a partially closed state. The result is a sieving processthat allows liquids and small particles to pass through the partiallyopen pylorus while indigestible particles that are larger than thepylorus are retropelled and retained in the stomach. This process causesthe stomach to retain particles that are greater than about 1 cm in sizefor about 4 to 6 hours. The prolonged-release matrix in theseembodiments of the invention is therefore selected as one that swells toa size large enough to be retropelled and thereby retained in thestomach, causing the prolonged release of the drug to occur in thestomach rather than in the intestines.

Disclosures of oral dosage forms that swell to sizes that will prolongthe residence time in the stomach are found in U.S. Pat. No. 5,007,790(“Sustained-Release Oral Drug Dosage Form,” Shell, inventor; Apr. 16,1991); U.S. Pat. No. 5,582,837 (“Alkyl-Substituted Cellulose-BasedSustained-Release Oral Drug Dosage Forms,” Shell, inventor; Dec. 10,1996); U.S. Pat. No. 5,972,389 (“Gastric-Retentive Oral Drug DosageForms for the Controlled Release of Sparingly Soluble Drugs andInsoluble Matter,” Shell et al., inventors; Oct. 26, 1999);International (PCT) Patent Application WO 98/55107 (“Gastric-RetentiveOral Drug Dosage Forms for Controlled Release of Highly Soluble Drugs,”Shell et al., inventors; publication date Dec. 10, 1998); U.S. patentapplication Publication No. US 2001/0018707 A1 (“Extending the Durationof Drug Release Within the Stomach During the Fed Mode,” Shell et al.,inventors, publication date Aug. 30, 2001); and International (PCT)Patent Application WO 96/26718 (“Controlled Release Tablet,” Kim,inventor: publication date Sep. 6, 1996). Each of the documents cited inthis paragraph is incorporated herein in its entirety.

In general, gastric-retentive (swellable) matrices contain binders thatare water-swellable polymers, and suitable polymers are those that arenon-toxic, that swell in a dimensionally unrestricted manner uponimbibition of water, and that release the drug gradually over time.Examples of polymers meeting this description are:

-   -   cellulose polymers and substituted cellulose polymers, including        alkyl-substituted, hydroxyalkyl-substituted, and        carboxyalkyl-substituted celluloses, specific examples being,        although not limited to, hydroxymethyl cellulose, hydroxyethyl        cellulose, hydroxypropyl cellulose, hydroxypropylmethyl        cellulose, and carboxymethylcellulose, and microcrystalline        cellulose    -   polysaccharides and substituted polysaccharides (with        substituents such as those listed above)    -   poly(alkylene oxide)s    -   chitosan    -   poly(vinyl alcohol)    -   xanthan gum    -   maleic anhydride copolymers    -   poly(vinyl pyrrolidone)    -   starch and starch-based polymers    -   maltodextrins    -   poly (2-ethyl-2-oxazoline)    -   poly(ethyleneimine)    -   polyurethane hydrogels    -   crosslinked poly(acrylic acid)s and substituted crosslinked        poly(acrylic acid)s (with substituents such as those listed        above)

Further examples are copolymers of the polymers listed above, includingblock copolymers and graft polymers. Specific examples of copolymers arePLURONIC® and TECTONIC®, which are polyethylene oxide-polypropyleneoxide block copolymers available from BASF Corporation, Chemicals Div.,Wyandotte, Mich., USA. Further examples are hydrolyzed starchpolyacrylonitrile graft copolymers, commonly known as “Super Slurper”and available from Illinois Corn Growers Association, Bloomington, Ill.,USA. Particularly preferred polymers are poly(ethylene oxide),hydroxypropyl methyl cellulose, and combinations of poly(ethylene oxide)and hydroxypropyl methyl cellulose.

The immediate-release portion of the dosage form is either a coatingapplied or deposited over the entire surface of a unitaryprolonged-release core, or a single layer of a tablet constructed in twoor more layers, one of the other layers being the prolonged-releasedportion. Immediate release of the drug from the immediate-release layeris achieved in any of a variety of ways. One example is by placing thedrug in a layer or coating that is sufficiently thin to allow fastpenetration by gastrointestinal fluid which then leaches the drug at arapid rate. Another example is by incorporating the drug in a mixturethat includes a supporting binder or other inert material that dissolvesreadily in gastrointestinal fluid, releasing the drug as the materialdissolves. A third is the use of a supporting binder or other inertmaterial that rapidly disintegrates into fine particles upon contactwith gastrointestinal fluid, with both the binder particles and the drugquickly dispersing into the fluid. Examples of materials that rapidlydisintegrate and disperse are lactose and microcrystalline cellulose.Hydroxypropyl methyl cellulose is a component that can serve both as asuspending agent and as a binder.

The dosage forms of this invention include those in which the same drugis used in both the immediate-release and the prolonged-release portionsas well as those in which one drug is formulated for immediate releaseand another drug, different from the first, is formulated for prolongedrelease. In cases involving the same drug, the invention serves toassure that the full immediate-release dosage of the drug is achievedrather than loss of the immediate-release effect. In cases involving onedrug for immediate release and a different drug for prolonged release,the invention prevents the two drugs from commingling to the detrimentof one or the other and assures that the full immediate-release dosageis achieved rather than a portion being lost to the prolonged-releaseregion of the dosage form.

This invention extends to both high-solubility and low-solubility drugs,as well as drugs that are combined with an additive that serves tosolubilize the drug or suspend it in a liquid carrier. Any of thesedrugs can be used as the immediate-release drug. Immediate-release drugsthat are either sparingly soluble or insoluble in water, regardless ofthe solubility of the prolonged-release drug, are of particular interestin certain embodiments of this invention. The immediate-release drug inthese dosage forms is of sufficiently low solubility that it remains asolid particle during the preparation of the dosage form. In certainembodiments of the invention, the dispersing medium is water or anaqueous solution that may contain other components. The term “at mostsparingly soluble” as used herein denotes a drug having a solubility inwater at 25° C. that is generally less than 2% by weight, preferablyless than 0.5% by weight. When the drug is in particulate form, thepreferred particle size is equal to or less than about 25 microns indiameter, more preferably equal to or less than about 10 microns indiameter, still more preferably within the range of from about 0.3micron to about 10 microns in diameter, and most preferably with therange of from about 1 micron to about 5 microns in diameter, all on aweight-average basis.

This invention is also applicable to dosage forms in which thedispersing medium for the immediate-release drug is an organic liquid,such as for example, ethanol, hexanes, chloroform, carbon tetrachloride,or dimethyl sulfoxide. An advantage of the use of a relatively volatileorganic liquid is a rapid rate of evaporation to leave a dry coating.Organic liquids are also useful for drugs that are unstable in aqueoussolutions.

The intermediate layer of drug-free polymer that serves as a barrier tomigration of the immediate-release drug into the prolonged-releasematrix during application of the immediate-release layer can be appliedover the prolonged-release segment as a solution or a suspension of thepolymer, in the same manner by which the immediate-release drug isapplied over the barrier layer. The polymer is one that is penetrable bygastrointestinal fluid and can be either soluble in gastrointestinalfluid or insoluble but erodible upon contact with gastrointestinalfluid, or simply insoluble. The polymer can also be one that swells uponimbibition of water in the same manner as the prolonged-release matrix.Polymers that are soluble or erodible in gastrointestinal fluid will bethose of which a sufficient amount remains during the formation of theimmediate-release layer to serve as a barrier until theimmediate-release layer is fully applied and dried. The ability of thepolymer to do this may vary with the thickness of the layer, themolecular weight of the polymer and, for swellable polymers, theswelling characteristics of the polymer. A small degree of swellabilitymay be favorable to accommodate any swelling of the prolonged-releasematrix that may occur during the application of the polymer over thematrix without creating fissures in the polymer layer.

The same polymers listed above for use as the matrix in theprolonged-release portion of the dosage form can be used in the barrierlayer. In many cases, it will be beneficial to use the same polymer asboth the prolonged-release matrix and the barrier layer, for purposes ofcompatibility between the core and the barrier. When the matrix is amixture of polymers, the barrier polymer can be one or more of thepolymers of the mixture. When the same polymer is used in both regions,a form of the polymer having a lower molecular weight is preferably usedin the barrier layer since a polymer of lower molecular weight will morereadily release the immediate-release drug to the gastric environment.Preferred polymers for use in forming the film are poly(ethylene oxide)hydroxypropyl methyl cellulose, poly(vinyl alcohol), combinations ofpoly(ethylene oxide) and hydroxypropyl methyl cellulose, andcombinations of poly(vinyl alcohol) and poly(ethylene oxide).

As noted above, the amount of the polymer in the intermediate layer mayaffect the barrier characteristics of the layer but it may also affectthe performance of the dosage form upon ingestion, i.e., theintermediate layer may further lower the rate of release of drug fromthe prolonged-release portion once the prolonged-release portion isexposed. In general, however, the amount can vary widely. In most cases,best results will be achieved when the weight ratio of the polymer inthe intermediate layer to the prolonged-release core is from about0.005:1 to about 0.2:1, preferably from about 0.01:1 to about 0.1:1, andmost preferably from about 0.01:1 to about 0.08:1.

The immediate-release drug can thus be deposited as a suspension or asolution over a unitary core of the prolonged-release drug coated withthe intermediate layer. Deposition can be achieved by coating techniquescommonly used in the pharmaceutical formulation art, such as spraying,pan coating, and the like. Alternatively, the immediate-release drug canbe combined with particles of a binding matrix and compressed over apreformed layer of the prolonged-release drug to form a layered tablet.In either case, the immediate-release coating or layer separatesrelatively quickly from the remainder of the tablet after ingestion,leaving the remainder intact.

The choice of drugs for use in either the prolonged-release orimmediate-release portions of the dosage form is not critical to theinvention, and many different types of drugs can be used. The selectionwill depend on the condition to be treated, the therapy being sought andthe needs of the particular patient. Drugs of high solubility in wateras well as drugs of low solubility can occupy either theprolonged-release or immediate-release portions. Examples ofhigh-solubility drugs are metformin hydrochloride, vancomycinhydrochloride, captopril, lisinopril, erythromycin lactobionate,ranitidine hydrochloride, sertraline hydrochloride, ticlopidinehydrochloride, baclofen, amoxicillin, cefuroxime axetil, cefaclor,clindamycin, levodopa, doxifluridine, tramadol, fluoxetinehydrochloride, bupropion, potassium chloride, and esters of ampicillin.Examples low solubility drugs are saguinavir, ritonavir, nelfinavir,thiamphenicol, ciprofloxacin hydrochloride, calcium carbonate,clarithromycin, azithromycin, ceftazidime, acyclovir, ganciclovir,cyclosporin, digoxin, paclitaxel, iron salts, topiramate, ketoconazole,and sulfonylureas such as glimepiride, glyburide, and glipizide. Otherdrugs suitable for use will be apparent to those skilled in the art.

One of the many areas of interest for this invention are combinations ofa diuretic and either an angiotensin converting enzyme inhibitor or anangiotensin II antagonist. Preferably, the angiotensin converting enzymeinhibitor or angiotensin II antagonist will occupy the immediate-releaseportion and the diuretic the prolonged-release portion, although forcertain patients a more appropriate dosage form may be one in which thediuretic occupies the immediate-release portion and the angiotensinconverting enzyme inhibitor or angiotensin II antagonist occupies theprolonged-release portion. Lisinopril is an example of an angiotensinconverting enzyme inhibitor, and examples of other similar drugs areenalapril, captopril, fosinopril, quinapril, ramipril, and benazepril.Losartan is an example of an angiotensin II antagonist, and examples ofother drugs of this class that might be used are valsartan, candesartan,irbesartan, telmisartan, and eprosartan. Loop diuretics, i.e., thoseacting on the sodium-potassium symporter in the ascending loop of Henlein the kidneys to decrease the rate of readsorption of water and sodium,are also of particular interest. Examples are furosemide, torsemide,ethacrynic acid, and bumetanide. Thiazides and thiazide-like diureticsare believed to act primarily on the sodium-potassium symporter in thedistal convoluted tubule. Examples of this type of diuretic arechlorothiazide and its sodium, salt, bendoflumethazide,hydroflumethazide, trichlorthiazide, chlorthalidone, indapamide,metolazone, quinethazone and hydrochlorothiazide. Potassium-sparingdiuretics act in the late distal tubule and collecting duct. Exampes areamiloride hydrochloride and triamterene.

Another class of combinations of particular interest is metforminhydrochloride as the prolonged-release drug, and a glitazone as theimmediate-release drug. Examples of glitazones are rosiglitazone(maleate), pioglitazone, and troglitazone. Yet another class ofcombinations is pyridoxine hydrochloride as the immediate-release drug,and a statin as the prolonged-release drug. Examples of statins areatorvastatin, simvastatin, pravastatin, lovastatin, cerivastatin,rosuvastatin, and fluvastatin. Of these, atorvastatin and simvastatinare preferred.

The amounts of drugs in the immediate-release and prolonged-releaseportions can vary widely, depending on the potencies of the drugs andthe desired dosage rates. Amounts of either drug in a single dosage formcan range from about 1 mg to about 1,000 mg. In most cases theappropriate amounts will range from about 5 mg to about 500 mg. Thisparagraph sets forth a number of examples, others of which will bereadily apparent to those skilled in the formulation and prescription ofthese drugs. In dosage forms that include furosemide, for example, orother drugs of similar potency as prolonged-release diuretics, apreferred dosage range of the diuretic is 10-120 mg. Lisinopril whenpresent is preferably in an amount of about 5 mg to about 40 mg.Losartan when present is preferably in an amount of about 10 mg to about100 mg. Loop diuretics when present are preferably in an amount of about5 mg to about 200 mg. When metformin hydrochloride is used as theprolonged-release drug with a glitazone in the immediate-release layer,a 500-mg metformin hydrochloride dose, for example, can be accompaniedby a 4-8-mg dose of a glitazone such as rosiglitazone maleate. In somecases, the amount of drug in the immediate-release portion will exceedthe amount in the prolonged-release portion. Dosage forms for examplethat contain pyridoxine hydrochloride as the immediate-release drug anda statin such as atorvastatin or simvastatin as the prolonged-releasedrug may contain 100-200 mg of pyridoxine hydrochloride and either 20-40mg of atorvastatin or 40-80 mg of simvastatin.

Preferred dosage forms in accordance with this invention are tablets,and the size, shape, and dimensions of the tablets are not critical tothe invention. In embodiments where a swellable matrix is used, thetablet upon swelling is preferably large enough to reach the dimensionsthat will cause it to be retained in the stomach during the fed mode.The tablet may be circular or elongated. An elongated tablet may be 18to 22 mm in length, 6.5 to 10 mm in width, and 6.2 to 7.5 mm in height.A specific example is one that is 20 mm in length, 6.7 mm in width, and6.4 mm in height. Again, these are merely examples; the shapes and sizescan be varied considerably.

Tablets in accordance with this invention can be prepared byconventional mixing, comminution, and tableting techniques that are wellknown in the pharmaceutical industry. The prolonged-release portion canfor example be fabricated by direct compression in punches and diesfitted to a rotary tablet press, or by ejection or compression molding,granulation followed by compression, or the formation of a paste that isthen extruded into a mold or into an extrudate which is then cut intoshort lengths. The intermediate (barrier) layer can be applied as acoating over the prolonged-release portion by spraying, dipping, orpan-coating, and the immediate-release portion can be applied as acoating over the intermediate layer by the same techniques, or as anadditional layer by tableting or compression in the same manner as theprolonged-release portion.

The following examples, both actual and prophetic, are offered forpurposes of illustration and are not intended to limit the scope of theinvention.

EXAMPLE 1

This example illustrates the preparation of tablets in accordance withthis invention that contain 500 mg metformin hydrochloride as theprolonged-release component and 1 mg glimepiride as theimmediate-release component.

Pre-formed tablets containing 500 mg of metformin hydrochloride in amatrix of hydroxypropyl methyl cellulose, poly(ethylene oxide),microcrystalline cellulose, and magnesium stearate were used as astarting material. A barrier layer solution was prepared by dissolvingOPADRY® YS-1-19025-A Clear (“OPADRY Clear,” hydroxypropyl methylcellulose, available from Colorcon, West Point, Pa., USA) in purifiedwater to a concentration of 8 weight percent. This solution was sprayedonto the metformin hydrochloride tablets until the tablet weightincreased by approximately 1%.

A suspension for applying the immediate-release layer was prepared bydissolving polyethylene sorbitan monooleate in purified water,dispersing glimepiride (micronized, 2-4 micron average particle size) inthe solution, and adding OPADRY Clear. The resulting suspensioncontained 0.24% polyethylene sorbitan monooleate, 0.20% glimepiride,7.56% OPADRY Clear, with water as the balance. The suspension wassprayed onto the barrier layer on the metformin hydrochloride tabletsuntil the tablet weight increased by approximately 4%.

EXAMPLE 2

This example likewise illustrates the preparation of tablets inaccordance with this invention that contain metformin hydrochloride asthe prolonged-release component and glimepiride as the immediate-releasecomponent, but with a higher amount of glimepiride (2 mg) than Example1.

Pre-formed metformin hydrochloride tablets identical to those used as astarting material in Example 1 were used. Likewise, an identical Opadrysolution was used as the barrier layer solution. This solution wassprayed onto the tablets to achieve a weight increase of 1%.

To prepare the immediate-release layer, a suspension similar to that ofExample 1 was prepared except that it contained 0.40% glimepiride ratherthan 0.20%. The suspension was sprayed onto the barrier layer until thetablet weight increased by approximately 4%.

EXAMPLE 3

This example illustrates the preparation of tablets in accordance withthis invention that contain 500 mg metformin hydrochloride as theprolonged-release component and 2 mg glimepiride as theimmediate-release component, but using a poly(vinylalcohol)-poly(ethylene oxide) poly(ethylene oxide) both as the barrierlayer and as a component in the immediate-release layer. The poly(vinylalcohol)-poly(ethylene oxide) used in the barrier layer is KOLLICOAT®IR, a product available from BASF Corporation, Chemicals Division,Wyandotte, Mich., USA.

Pre-formed metformin hydrochloride tablets identical to those used as astarting material in the preceding examples are used. The barrier layersolution is then prepared by dissolving the KOLLICOAT IR in purifiedwater to a concentration of 8% by weight. This solution is then sprayedonto the pre-formed tablets to achieve a weight increase of 1%.

The immediate-release drug-containing coating suspension is prepared bydissolving polyethylene sorbitan monooleate in purified water,dispersing glimepiride (micronized, 2-4 micron average particle size) inthe solution, adding KOLLICOAT IR, and mixing the suspension for 45-60minutes to allow the suspension to aerate. The resulting suspensioncontains 0.24% polyethylene sorbitan monooleate, 0.20% glimepiride,7.56% KOLLICOAT, with water as the balance. The suspension is sprayedonto the barrier layer until the tablet weight increases byapproximately 6%.

EXAMPLE 4

This example illustrates the preparation of tablets in accordance withthis invention that contain 20-40 mg atorvastatin as theprolonged-release component and 100-200 mg pyridoxine hydrochloride asthe immediate-release component, again using KOLLICOAT IR both as thebarrier layer and as a component in the immediate-release layer.

Pre-formed atorvastatin tablets containing 20 or 40 mg in a matrix ofhydroxypropyl methyl cellulose, poly(ethylene oxide), microcrystallinecellulose, and magnesium stearate are used as a starting material. Thebarrier layer solution is then prepared by dissolving the KOLLICOAT IRin purified water to a concentration of 8% by weight. This solution issprayed onto the pre-formed tablets to achieve a weight increase of0.5-2%.

The immediate-release drug-containing coating suspension is prepared bydissolving with mixing the required amount of pyridoxine hydrochloridein purified water, then adding KOLLICOAT with further mixing anddeacration. The resulting solution is applied to the barrier layer untilthe tablet weight increases by approximately 6%.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those skilled in the art that further drugs canbe included, and that the shapes, components, additives, proportions,methods of formulation, and other parameters described herein can bemodified further or substituted in various ways without departing fromthe spirit and scope of the invention.

1. A method for the manufacture of a pharmaceutical tablet which uponoral ingestion delivers a first drug by immediate release and a seconddrug by prolonged release defined as a release rate intogastrointestinal fluid that is slow enough to leave at least about 40%of said second drug unreleased one hour after ingestion, said methodcomprising: (a) dispersing said second drug in a solid matrix to form aunitary body which upon immersion in gastrointestinal fluid releasessaid second drug by prolonged release; (b) depositing on a surface ofsaid unitary body a polymeric film that is devoid of either said firstdrug or said second drug; (c) depositing over said polymeric film afluid medium comprising said first drug and a liquid carrier that doesnot remove said polymeric film upon contact therewith; and (d)evaporating said liquid carrier from said fluid medium thus deposited toleave a solid layer containing said first drug over said unitary body.2. The method of claim 1 in which said solid matrix is a member selectedfrom the group consisting of celluloses, substituted celluloses,microcrystalline cellulose, polysaccharides, substitutedpolysaccharides, polyl(alkylene oxide)s, poly(vinyl alcohol), starch,starch-based polymers, crosslinked poly(acrylic acid)s, and substitutedcrosslinked poly(acrylic acid)s.
 3. The method of claim 1 in which saidsolid matrix is a member selected from the group consisting ofpoly(ethylene oxide), hydroxypropyl methyl cellulose, and combinationsof poly(ethylene oxide) and hydroxypropyl methyl cellulose.
 4. Themethod of claim 1 in which said polymeric film is a member selected fromthe group consisting of poly(ethylene oxide), hydroxypropyl methylcellulose, polyvinyl alcohol, combinations of poly(ethylene oxide) andhydroxypropyl methyl cellulose, and combinations of polyvinyl alcoholand poly(ethylene oxide).
 5. The method of claim 1 in which said fluidmedium comprises a liquid solution of said first drug in a solvent. 6.The method of claim 1 in which said fluid medium comprises a liquidsolution of said first drug and a polymer in a solvent.
 7. The method ofclaim 1 in which said fluid medium comprises a suspension of said firstdrug in solid particle form in a liquid suspending agent.
 8. The methodof claim 1 in which said fluid medium comprises a suspension of saidfirst drug in solid particle form and a dispersing agent, also in solidparticle form, in a liquid suspending agent, said dispersing agent beinga substance that separates into discrete particles upon contact withgastrointestinal fluid.
 9. The method of claim 1 in which said fluidmedium is an aqueous suspension of said first drug, and said first drugis comprised of particles having a weight-averaged diameter equal to orless than 25 microns.
 10. The method of claim 1 in which said fluidmedium is an aqueous suspension of said first drug, and said first drugis comprised of particles having a weight-averaged diameter equal to orless than 10 microns.
 11. The method of claim 1 in which the weightratio of said polymeric film to said unitary body is from about 0.005:1to about 0.2:1.
 12. The method of claim 1 in which the weight ratio ofsaid polymeric film to said unitary body is from about 0.01:1 to about0.1:1.
 13. The method of claim 1 in which the weight ratio of saidpolymeric film to said unitary body is from about 0.01:1 to about0.08:1.
 14. The method of claim 1 in which (b) comprises surroundingsaid unitary body entirely with said polymeric film, and said solidlayer of (d) is a shell completely encasing said unitary body andpolymeric film.
 15. The method of claim 1 in which (b) and (c) comprisedepositing said polymeric film and said first drug over only a portionof the entire surface of said unitary body, leaving the remainder ofsaid unitary body exposed.
 16. The method of claim 1 in which saidliquid carrier of step (c) is water.
 17. The method of claim 1 in whichsaid liquid carrier of step (c) is an organic solvent.
 18. The method ofclaim 17 in which said organic solvent is a member selected from thegroup consisting of ethanol, hexanes, chloroform, carbon tetrachloride,and dimethyl sulfoxide.
 19. A dosage form for delivering a first drugthat is immediately releasable upon ingestion and a second drug that isreleasable by prolonged release defined as a release rate that is slowenough to leave at least about 40% of said second drug unreleased onehour after ingestion, said dosage form comprising: a prolonged-releasesection comprising said second drug dispersed in a solid matrix thatreleases said second drug by prolonged release upon immersion of saiddosage form in gastrointestinal fluid; a polymeric film adhering to asurface of said prolonged-release section, said polymeric film beingpenetrable by gastrointestinal fluid and devoid of both said first drugand said second drug; and an immediate-release section comprising asolid layer adhering to said polymeric film, said solid layer comprisingsaid first drug dispersed in a matrix that promotes immediate release ofsaid first drug upon immersion of said dosage form in gastrointestinalfluid.
 20. The dosage form of claim 19 in which said solid matrix is amember selected from the group consisting of celluloses, substitutedcelluloses, microcrystalline cellulose, polysaccharides, substitutedpolysaccharides, polyl(alkylene oxide)s, poly(vinyl alcohol), starch,starch-based polymers, crosslinked poly(acrylic acid)s, and substitutedcrosslinked poly(acrylic acid)s.
 21. The dosage form of claim 19 inwhich said solid matrix is a member selected from the group consistingof poly(ethylene oxide), hydroxypropyl methyl cellulose, andcombinations of poly(ethylene oxide) and hydroxypropyl methyl cellulose.22. The dosage form of claim 19 in which said polymeric film is a memberselected from the group consisting of poly(ethylene oxide),hydroxypropyl methyl cellulose, polyvinyl alcohol, combinations ofpoly(ethylene oxide) and hydroxypropyl methyl cellulose, andcombinations of polyvinyl alcohol and poly(ethylene oxide).
 23. Thedosage form of claim 19 in which said solid matrix of said unitary bodyis defined as a first solid matrix and said fluid medium comprises saidfirst drug in particle form and a second solid matrix, also in particleform, said second solid matrix being a substance that separates intodiscrete particles upon immersion in gastrointestinal fluid.
 24. Thedosage form of claim 19 in which the weight ratio of said polymeric filmto said unitary body is from about 0.005:1 to about 0.2:1.
 25. Thedosage form of claim 19 in which the weight ratio of said polymeric filmto said unitary body is from about 0.01:1 to about 0.1:1.
 26. The dosageform of claim 19 in which the weight ratio of said polymeric film tosaid unitary body is from about 0.01:1 to about 0.08:1.
 27. The dosageform of claim 19 in which said polymeric film and said immediate-releasesection constitute a shell that fully encases said prolonged-releasesection.
 28. The dosage form of claim 19 in which said polymeric filmand said immediate-release section cover a portion of the surface ofsaid prolonged-release section, leaving the remainder of saidprolonged-release section exposed.
 29. The dosage form of claim 19 inwhich one of said first and second drugs is a diuretic and the other isa member selected from the group consisting of angiotensin convertingenzyme inhibitors and angiotensin II antagonists.
 30. The dosage form ofclaim 29 in which said diuretic is a loop diuretic.
 31. The dosage formof claim 30 in which said loop diuretic is a member selected from thegroup consisting of furosemide, torsemide, ethacrynic acid, andbumetanide.
 32. The dosage form of claim 29 in which said diuretic is athiazide diuretic.
 33. The dosage form of claim 34 in which saidthiazide diuretic is a member selected from the group consisting ofchlorothiazide, bendoflumethazide, hydroflumethazide, trichlorthiazide,chlorthalidone, indapamide, metolazone, quinethazone andhydrochlorthiazide.
 34. The dosage form of claim 29 in which saiddiuretic is a potassium-sparing diuretic.
 35. The dosage form of claim34 in which said potassium-sparing diuretic is a member selected fromthe group consisting of amiloride hydrochloride and triamterene.
 36. Thedosage form of claim 19 in which said first drug is a member selectedfrom the group consisting of lisinopril and losartan, and said seconddrug is a diuretic.
 37. The dosage form of claim 19 in which said firstdrug is a glitazone, and said second drug is metformin hydrochloride.38. The dosage form of claim 19 in which said first drug is pyridoxinehydrochloride, and said second drug is a member selected from the groupconsisting of atorvastatin, simvastatin, pravastatin, lovastatin,cerivastatin, rosuvastatin, and fluvastatin.
 39. The dosage form ofclaim 19 in which said first drug is pyridoxine hydrochloride, and saidsecond drug is a member selected from the group consisting ofatorvastatin and simvastatin.
 40. The dosage form of claim 19 in whichsaid second drug is a member selected from the group consisting ofmetformin hydrochloride, vancomycin hydrochloride, captopril,erythromycin lactobionate, ranitidine hydrochloride, sertralinehydrochloride, ticlopidine hydrochloride, amoxicillin, cefuroximeaxetil, cefaclor, clindamycin, doxifluridine, tramadol, fluoxitinehydrochloride, ciprofloxacin hydrochloride, gancyclovir, bupropion,lisinopril, cefaclor, saguinavir, ritonavir, nelfinavir, clarithromycin,azithromycin, ceftazidine, cyclosporin, digoxin, paclitaxel, iron salts,topiramate, and ketoconazole.
 41. The dosage form of claim 19 in whichsaid second drug is a member selected from the group consisting oflisinopril, enalapril, captopril, fosinopril, quinapril, ramipril, andbenazepril.
 42. The dosage form of claim 19 in which said second drug isa member selected from the group consisting of losartan, valsartan,candesartan, irbesartan, telmisartan, and eprosartan.
 43. The dosageform of claim 19 in which said first drug is a sulfonylurea selectedfrom the group consisting of glimepiride, glyburide, and glipizide, andsaid second drug is metformin hydrochloride.
 44. The dosage form ofclaim 19 in which said first drug is glimepiride and said second drug ismetformin hydrochloride.
 45. The dosage form of claim 19 in which saidfirst drug is glyburide and said second drug is metformin hydrochloride.46. The dosage form of claim 19 in which said first drug is glipizideand said second drug is metformin hydrochloride.